Pretreatment of mice with intravenous injections of deaggregated hens' ovalbumin(OVA) in a wide range of doses(lug to lmg) failed to affect in a major way the magnitude of antibody responses of mice of high-responder inbred strains to subsequent intraperitoneal immunization with low doses of OVA in A1(OH)3 adjuvant. In contrast, pretreatment of mice with a single intragastric(IG) exposure to 20mg of OVA, totally abolished subsequent primary and secondary responses to either low (lug) or high (50ug) doses of OVA plus A1(OH)3 given intraperitoneally. Preliminary experiments demonstrated that: (a) IG-exposure to OVA induces unresponsiveness better in high-responder rather than in low-responder strains; (b) IG-exposure to hapten-protein conjugates induces unresponsiveness in carrier-specific T-cells; however, the responsiveness of hapten-specific B-cells is not reduced and may be increased; (c) the amounts of antigenically-intact materials absorbed from the gut to the circulation after IG-exposure to protein antigens are well below 1% of the challenge dose; these amounts fail to induce unresponsiveness if injected intravenously in the form of deaggregated antigen solutions. The efficiency of the induction of immune unresponsiveness to potent protein immunogens by digestive route is undoubtedly more impressive than that associated with previously described methods. This will allow the performance of critical experiments in the investigation of cellular and genetic aspects of the control of immune responsiveness. In addition, the phenomenon has a potentially broad physiologic significance.